Hyperviscosity of blood due to elevated plasma or serum viscosity is associated with serum immunoglobulin abnormalities and is manifested clinically by a combination of ocular, hematologic, neurologic, cardiovascular, and renal symptoms which are referred to as the hyperviscosity syndrome. This syndrome is a frequent complication in neoplastic plasma cell dyscrasias such as Waldenstrom's macroglobulinemia and multiple myeloma; it has also been observed in hyperplastic connective tissue diseases such as rheumatoid arthritis. In order to better define the mechanisms which cause serum hyperviscosity we propose a detailed study of the physical, biochemical, and immunochemical properties of some immunoglobulins which are associated with such large increases in serum viscosity that clinical signs of the hyperviscosity syndrome are present. Physico-chemical and primary structural analyses would be done in order to (1) assess the role of immunoglobulin size, conformation, and concentration as contributing factors in serum hyperviscosity (2) characterize the intermediate complexes and/or high molecular weight aggregates which are formed by many hyperviscosity-associated immunoglobulins, analyze them for antibody activity, and elucidate the nature and structure of the polymerizing sites on such molecules; and (3) gain insight into why some of these proteins also exhibit cryoprecipitable properties. Our broad objectives are to contribute to the fundamental knowledge of (1) the forces that influence the three-dimensional structure of proteins, (2) the relationship between protein structure and physiological/immunological function, and (3) how structural alterations may so disrupt the conformation of biologically active macromolecules that their normal function is impaired and clinical problems ensue. Another objective is that some of the knowledge derived from basic studies of this type be applied towards improving the management of certain hematologic and cardiovascular problems encounted in patients with hyperviscosity syndromes.